Alpha-halo-alpha-amino ketones



United States Patent 3,494,964 a-HALO-a-AMINO KETONES William W.Hargrove, Indianapolis, Ind., assignor to Eli Lilly and Company,Indianapolis, Ind., a corporation of Indiana No Drawing. Originalapplication Oct. 22, 1965, Ser. No. 502,331. Divided and thisapplication Jan. 13, 1969, Ser. No. 790,852

Int. Cl. C07c 97/02, 87/50; A61k 27/00 U.S. Cl. 260-584 Claims ABSTRACTOF THE DISCLOSURE a-Halo-a-amino ketones of the formula RLIT'H RLCCCHR4wherein R R R R and X are as hereinbelow defined,

useful as intermediates in the preparation of2,2-disubstituted-3-azetidinones and 2,2-disubstituted-azetidines.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisionalapplication of my copending application Ser. No. 502,331, filed Oct. 22,1965. Another divisional application of application Ser. No. 502,331 isapplication Ser. No. 790,856, filed Jan. 13, 1969.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novalazetidinones and to intermediates useful in the preparation thereof.More particularly, it relates to 2,2-disubstituted 3-azetidinones,2,2,3- trisubstituted azetidines, and 2,2,3,3-tetasubstituted azetidinesderivable therefrom.

The preparation of certain 3-substituted 2-azetidinones isomeric withthe compounds of the present invention is recorded by Testa et al. inAnn., 614, 158166 (1958), and in Ann., 625, 95-98 (1959). The sameauthor, in US. Patent 3,076,799 (Feb. 5, 1963), teaches the preparationof 3,3-disubstituted azetidines from the 3-substituted 2-azetidinones.Additionally, l-acyl 3-substituted azetidines are described by Testa etal. in US. Patent 3,037,019 (May 29, 1962). Other 1,3-disubstitutedazetidines are described by Testa et al. in US. Patent 3,028,378 (Apr.3, 1962). To date, however, the art does not appear to reveal thateither the 2,2-disubstituted 3- azetidinones, the 2,2,3-tn'substitutedazetidines, or the 2,2,3,3-tetrasubstituted azetidines derivabletherefrom, as taught herein, have ever been prepared.

It is an object of this invention to furnish novel 2,2- disubstituted3-azetidinones which are hypotensive agents.

Another object is to provide a process for the synthesis of2,2-disubstituted 3-azetidinones. A further object is to providetad-halo a-amino ketones, useful as intermediates in the synthesis of2,2-disubstituted 3-azetidinones. Another object is to provide novel2,2,3-trisubstituted and 2,2,3,3-tetrasubstituted azetidines possessingactivity as CNS stimulants.

In fulfillment of the above and other objects, this invention provides agroup of novel compounds of the fol- 3,494,964 Patented Feb. 10, 1970"ice lowing Formulas I, II, and III, or the acid addition salts thereof:

RLNH R N R R -N R* R C(|1HR I I l R o X F R O R R I II III wherein R andR when taken separately, represent C C alkyl, C C cycloalkyl, alkoxy(C C)alkyl, or phenyl;

R and R when taken together with the carbon atoms to which they areattached, represent C -C cycloalkyl;

R represents hydrogen, C -C alkyl, C -C cycloalkyl, or phenyl;

R represents hydrogen, C C alkyl, C -C cycloalkyl, or alkoXy(C -C)alkyl;

R represents hydrogen, hydroxy, cyano, halogen, or C -C alkanoyloxy;

R represents hydrogen, hydroxy, C -C alkyl, di(C -C alkyl)amino, C Calkyloxy, C C cycloalkyl, phenylsub'stituted C C alkyl, or phenyl; and

X represents bromine or chlorine.

The acid addition salts of the bases represented by the above formulascan be prepared employing for example the following acids: hydrochloric,hydrobromic, hydriodic, sulfuric, phosphoric, oxalic, and the like, allof which are generally regarded as forming pharmaceutically acceptableacid addition salts.

In the above formulas, C C alkyl can be illustrately methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, namyl, isoamyl, t-amyl and thelike.

The phenyl ring may have a wide variety of substituents withoutdeparting from the spirit of the invention, including halogens, such aschlorine, bromine, iodine, and fluorine; C -C alkyl groups, such asthose illustrated above; haloalkyl, such as trifluoromethyl,trichloromethyl, pentafluoroethyl, iodomethyl, bromoethyl,dichloromethyl and the like; and alkoxy, such as methoxy, ethoxy,propoxy, isopropoxy, n-butoxy and the like. Thus, illustrativesubstituted phenyl groups can include o-iodophenyl, rn-fluorophenyl,o-chlorophenyl, o-brornophenyl, mbromophenyl, p-bromophenyl, p-tolyl,o-isoamylphenyl, rn-xylyl, p-iodophenyl, m-trifluoromethylphenyl,p-pentafluoroethylphenyl, p trichloromethylphenyl, m ethoxyphenyl,anisyl, and the like.

In the above formulas, C -C alkanoyloxy refers to acetoxy, propionoxy,butyroxy, valeryloxy, isobutyroxy, and isovaleryloxy.

In the above formulas, C -C alkyloxy refers to the C -C alkyl groupsabove, attached at any available position of the defined C -C alkylgroup through an intervening oxygen atom. They may includeillustratively methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.-butoxy, tert.-butoxy, n-amyloxy, isoamyloxy,sec.-amyloxy, and tert.-amyloxy.

Lower alkoxy (C -C alkyl refers to the lower alkyl groups methyl, ethyl,n-propyl, or isopropyl, attached at any available position of thedefined lower alkyl group through an intervening oxygen atom to a C -Calkyl group as defined above, and can be illustratively methoxyethyl,methoxypropyl, ethoxymethyl, ethoxyethyl, npropoxybutyl, ethoxy-n-amyl,n-butoxyethyl, and the like.

Phenyl-substituted C -C alkyl can be illustratively benzyl,,8-(m-xy1yl)ethyl, phenethyl, p-bromophenethyl, m-chlorobenzyl,m-ethylphenethyl, :p-isopropylbenzyl, pmethoxyphenethyl,m-ethoxyphenethyl, p-propoxybenzyl, and the like.

In the above formulas, the cycloalkyl rings can be illustrativelycyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,methylcyclopentyl, ethylcyclohexyl and the like.

The novel compounds illustrated by Formula I, supra, are obtained byhalogenation in acetic acid solution of an a-amino ketone in the form ofits acid addition salt as illustrated by Reaction Sequence I:

Reaction Sequence I The starting a-amino ketone (A) in Reaction SequenceI is conveniently prepared according to the method of Easton et al., US.Patent 3,067,101 (1962).

The preparation of I is conveniently carried out by allowing thehalogen, for example, bromine, to react with the a-amino ketone acidaddition salt in glacial acetic acid solution to yield the ot'-bromoa-amino ketone hydrobromide, which separates from the reaction productmixture, is filtered off, and recrystallized from a suitable solvent.Owing to the inherent instability of an tad-halo a-aminO ketone, it ispreferably kept in the form of its acid addition salt.

In a preferred method of synthesis, the a-amino ketone acid additionsalt is dissolved in glacial acetic acid, the solution stirred andcooled in an ice bath, and gaseous hydrogen bromide introduced into thesolution for about 30 minutes. The reaction mixture is allowed to warmto ambient room temperature, bromine added dropwise with stirring over aperiod of about one hour, and stirring continued for 5 additional hours.The cU-halo aamino ketone hydrobromide, which separates from thereaction product mixture, is filtered off and recrystallized fromchloroform. The excess hydrogen bromide added during the process hasbeen found to aid in the utilization of the a-amino ketone to yield thea'-halo a-amino ketone.

While this method of treating a ketone with a halo genating agent is awell-known reaction, the application to a-amino ketones appears to benew, there being no indication in the art of the halogenation of ana-amino ketone by this procedure, which procedure serves to providenovel compounds previously unavailable by any other method.

Where R represents phenyl-substituted C -C alkyl in Formula I, supra,difliculty is encountered in preparing the a-halo a-amino ketones by thedescribed process, as halogenation appears to take place not only on themethylene carbon adjacent to the carbonyl but extraneously in thephenyl-substituted C C alkyl group. To obviate this difficulty and tomake it possible to provide a wide range of intermediates useful inpreparing the novel azetidinones and derivatives of this invention, anovel method of synthesis of the desired ketones has been developed.This method is described more fully in the copending application ofEaston et al., Ser. No. 502,359, filed this even date. In the Easton etal., process, a solution of an acylamido acetylene in an inert solventis treated with a halogenating agent such as bromine, chlorine, oriodine to obtain the a'-halo a-amino ketone represented by Formula I inthe form of its acid addition salt.

The a'-halo a-amino ketones synthesized by the methods outlined aboveare useful as intermediates in the preparation of the novel3-azetidinones (II) of this invention according to Reaction Sequence IIwhich fol lows:

Reaction Sequence II In both Reaction Sequence I and Reaction SequenceII, R R R R and X have the same meanings as hereinbefore.

Reaction Sequence II is conveniently carried out by allowing the a'-haloa-a mino ketone (I) acid addition salt to react in dimethylformamidewith a mild base, illustratively, sodium bicarbonate, under anatmosphere of nitrogen, the nitrogen atmosphere being used to protectthe azetidinone from oxidation by air. The said reaction mixture isstirred for about 30 minutes, then water is added dropwise until thevolume of the reaction mixture is doubled, and stirring is continuedunder nitrogen for 2 additional hours to assure substantial completionof the reaction. The water aids in solubilizing the reactants andbringing the reaction to completion.

The 3-azetidinone produced thereby is isolated by diluting the basicsolution with water and then making the solution more strongly basic.The aqueous solution is shaken with ether to extract the basicnitrogenous product. The ether extracts are washed with water, and thebasic nitrogenous product is extracted from the ether with diluteaqueous hydrochloric acid, thus 'forming the acid addition salt of the3-azetidinone. The aqueous acid solution is washed once with ether toremove impurities, then made basic with aqueous sodium hydroxide, andthe crude amine product is extracted with ether. The ether solution iswashed once with water and then dried by adding dry benzene anddistilling in -vacuo, thus azeotropically distilling with the benzeneany water present. The oily residue is then fractionally distilled,suitably through a spinning-band column at reduced pressure. The3-azetidinones darken rapidly in air, apparently decomposing in theprocess, and are therefore handled as little as possible after beingdistilled. The acid addition salts can be conveniently prepared bymethods well-known to the art, the salts thus providing stable forms inwhich the 3-azetidinones can be kept.

The novel substituted azetidines represented by Formula III, supra, canbe prepared utilizing the unique reactivity exhibited by the carbonylgroup, a reactivity enhanced by the location of said carbonyl groupopposite a nitrogen atom in a four-membered heterocyclic ring. Thiscarbonyl group undergoes a number of well-known addition reactions, forexample, with the elements of water, alcohol, or hydrogen cyanide, toyield hydrates, alcoholates (hemiketals) or cyanhydrins, respectively.The 3-azetidinones also react readily with Grignard reagents andorganolithium compounds to yield the expected tertiary alcohols. Thecarbonyl group can be reduced using a reagent such as sodium borohydrideto yield the I i-azetidinol, and the said azetidinol can in turn behalogenated with a reagent such as thionyl chloride to produce a3-chloroazetidine.

The 3-azetidinols behave as do other alkanols or cycloalkanols in beingreadily esterified by treatment with an acid anhydride.

The novel 3-azetidinones have interesting hypotensive activity. Inaddition, they serve as intermediates in the preparation of the novel3-azetidinols and azetidines represented by Formula III above. Theazetidinols possess CNS stimulant properties and the azetidines areblood pressure-lowering agents.

The hypotensive properties of the novel compounds of this invention canbe utilized by administering the compounds in a composition adapted fororal or parenteral administration, oral administration being especiallypreferred because of the ease and convenience associated therewith.Thus, the compositions can be in the form of a compressed tablet or afilled capsule, as well as in the form of a solution or suspensionsuitable for oral or intramuscular administration.

The interesting hypotensive activity is shown when the compounds areadministered orally to rats made hypertensive by the well-knownGoldblatt method. Doses of 20-40 mg./kg. orally cause a significantlowering of the blood pressure in the test animals.

The novel compounds possessing CNS stimulant properties can be utilizedby administration in a form adapted for intra-peritoneal administration.Thus, the compounds can be in the form of a solution or suspensionsuitable for intra-peritoneal administration.

The CNS stimulant properties are shown when the compounds areadministered intra-peritoneally to mice in doses of 100 mg./kg. Thesedosages produce an increase in the rate of respiration, somevasodilatation, and an increased irritability of the test animals.

The invention is further illustrated by the following specific examples.

EXAMPLE 1 3-t-butylamino-3-methyl-1-bromo-2-butanone hydrobromide To41.4 g. of 3-t-butylamino-3-methyl-2-butanone contained in a one-liter,three-neck flask equipped with mechanical stirrer and protected fromatmospheric moisture were added 300 ml. of glacial acetic acid. Thereaction mixture was cooled in an ice bath, and dry hydrogen bromide gaswas passed into the stirred mixture for about one-half hour. The tubefor introducing the hydrogen bromide was then replaced with a droppingfunnel protected from atmospheric moisture. Through the dropping funnel,42.0 g. of bromine were added dropwise to the stirred mixture at roomtemperature over a period of one hour. Crystalline material began toappear after about one-half the bromine had been added.

When addition was complete, the reaction mixture was allowed to stir atambient room temperature for five additional hours.

The crude, crystalline product, after being filtered off and presseddry, Weighed 81.3 g. After being recrystallized from chloroform, the3-t-butylamino-3-methyl-1-bromo-2- butanone hydrobromide had a meltingpoint of about 165 C. (dec.) and weighed about 80.8 g.

Amzlysis.Calcd.: C, 34.09%; H, 6.04%; Br, 50.4%. Found: C, 34.35%; H,6.27%; Br, 50.08%.

EXAMPLE 2 1-t-butyl-2,2-dimethyl-3-azetidinone A mixture of 24 g. ofsodium bicarbonate and 100 ml. of dimethylformamide was prepared in a500 ml., threeneck, round-bottom flask equipped with a mechanicalstirrer, an inlet tube through which nitrogen was introduced, and adropping funnel. To the stirred mixture under a nitrogen atmosphere wasadded in one portion a solution composed of 23.7 g. of3-t-butylamino-3-methyll-brorno-Z-butanone hydrobromide dissolved in 50ml. of dimethylformamide. After stirring under nitrogen for about 30minutes, water was added dropwise until the volume of the mixture haddoubled. Some warming of the reaction mixture occurred. Stirring wascontinued under nitrogen for two additional hours.

6 The reaction product mixture was worked up by diluting the basicsolution with an equal volume of water and extracting three times withml. portions of ether. The aqueous layer was then made strongly basicwith sodium hydroxide and extracted twice more with 100 ml. portions ofether. The combined ether extracts, containing the crude amine product,were washed once with about 100 m1. of water and then extracted withabout 150 ml. of dilute, aqueous hydrochloric acid, thus forming thehydrochloride salt of the 3-azetidinone. The aqueous acidic solution waswashed with about 150 ml. of ether to remove impurities, and then theaqueous layer was made basic with sodium hydroxide. The basic mixturewas extracted wtih three 100 ml. portions of ether to recover the crudeproduct and the aqueous layer was discarded. The combined ether extractswere washed once with 100 ml. of distilled water. The ether solvent wasremoved by distillation under nitrogen and the oily residue dried byazeotropic distillation of any water present with about 5 0l00 m1. ofbenzene, again under nitrogen. Final fractional distillation was doneusing a 24-inch spinning band column. l-t-butyl2,2-dimethyl-3azetidinone having a boiling point of about 96 C./51 mm.and n =1.4388 was obtained. The structure was confirmed by infrared andNMR spectra and by elemental analysis.

Analysis.Calcd.: C, 69.60%; H, 11.04%; N, 9.03%. Found: C, 70.40%; H,11.16%; N, 9.29%.

The 3-azetidinone free base darkens rapidly in air, apparentlydecomposing in the process. It was, therefore, exposed to the atmosphereas little as possible after being distilled.

A 3.0 g. sample of 1-t-butyl-2,2-dimethyl-3-azetidinone was dissolved inabout 50 ml. of chloroform and treated with an ethanolic hydrogenchloride solution at 0 C. The solvents were removed in vacuo, and thecrude residue was recrystallized from methyl ethyl ketone underanhydrous conditions to yield 1-t-butyl-2,2-dimethyl-3- azetidinonehydrochloride as a solid having a melting point of about 118 C., andweighing 2.3 g. The structure was confirmed by the infrared spectrum.

EXAMPLE 3 1-t-butyl-2,2-dimethyl-3,3-azetidinediol hydrochlorideRecrystallization of crude 1 t butyl-2,2-dimethyl-3- azetidinonehydrochloride from a mixture of acetone, water, and methyl ethyl ketoneyielded 1-t-butyl-2,2-dimethyl-3,3-azetidinediol hydrochloride having amelting point of about 122l23 C. The product was identified by theinfrared spectrum and elemental analysis.

Analysis.Calcd.: C, 51.70%; H, 9.60%; O, 15.24%. Found: C, 52.33%; H,9.78%; O, 15.45%.

EXAMPLE 4 1t-butyl-2,2-dimethyl-3-azetidinol A solution of 9 g. ofsodium borohydride in ml. of anhydrous methanol was prepared in a 500ml. threeneck flask cooled to 0 C. To this solution 1-t-buty1-2,2-dimethyl-3-azetidinone, 4.1 g., dissolved in 50 ml. of anhydrousmethanol, was added dropwise with stirring. When the addition wascomplete, the cooling bath was removed. As the mixture warmed graduallyto room temperature, a vigorous reaction occurred. When this reactionhad subsided, the mixture Was refluxed for about two hours.

The reaction product mixture was cooled to room temperature, dilutedwith an equal volume of water, and acidified (pH=2) with aqueous 10percent hydrochloric acid. Most of the solvent methanol was removed invacuo leaving a semisolid residue. The residue was dissolved in waterand the solution washed three times with 100-ml. portions of ether toremove unwanted impurities. The aqueous solution was basified withsodium hydroxide,

extracted with three 100-ml. portions of chloroform, dried, and thesolution acidified by adding ethanolic hydrogen chloride thereto. Thesolvents were removed in vacuo leaving a residue. The residue wastriturated with ether and a crude crystalline material was filtered oil?and recrystallized from a mixture of methyl ethyl ketone and methanol toyield 2.5 g. of 1 t butyl-2,2-dimethyl-3- azetidinol hydrochloridehaving a melting point of about 152l53 C. with slow decomposition.

Analysis.Calcd.: C, 55.80%; H, 10.41%; N, 7.23%. Found: C, 55.75%; H,10.30%; N, 7.29%.

EXAMPLE 5 1-t-butyl-2,2-dimethyl-3-chloroazetidine A suspension of g. ofl-t-butyl 2,2 dimethyl-3- azetidinol hydrochloride in 60 ml. of carbontetrachloride was prepared in a small flask, and 14.8 g. of thionylchloride were added. The mixture was swirled and warmed on the steambath until complete solution of all solid material had occurred. It wasthen refluxed on the steam bath for about six hours.

The solvent was removed in vacuo and the brown residue recrystallizedfrom ethyl acetate, using decolorizing carbon in the process. A total ofabout 4 g. of brown, crystalline product was obtained. The infraredspectrum was compatible with the structure of l-t-butyl-2,2-dimethyl-3-chloroazetidine hydrochloride.

EXAMPLE 6 l-t-butyl-2,2-dimethyl-3 -acetoxyazetidine A mixture of 510mg. of l-t-butyl 2,2 dimethyl-3- azetidinol hydrochloride and 5 ml. ofacetic anhydride was heated on the steam bath for about two hours. Theexcess acetic anhydride was removed in vacuo to leave a crystallinesolid residue of crude l-t-butyl-2,2-dimethyl- 3-acetoxyazetidinehydrochloride. This material was recrystallized from methyl ethyl ketoneand had a melting point of about 155-1555 C. with decomposition.

Analysis.Calcd.: C, 56.04%; H, 9.40%; N, 5.94%. Found: C, 56.71%; H,9.58%; N, 6.15%.

EXAMPLE 7 1-t-butyl-2,2-dimethyl-3-phenylazetidine A Grignard reagentwas prepared in about 150 ml. of ether under a nitrogen atmosphere from8.95 g. of bromobenzene and 1.44 g. of magnesium turnings. To the resulting Grignard reagent were added 4.0 g. of solidl-tbutyl-2,2-dimethyl 3-chloroazetidine hydrochloride portionwise atroom temperature with stirring, and stirring was continued for two hoursafter the addition was complete. The reaction product mixture wastreated with dilute hydrochloric acid and the ether layer was separatedand washed with Water.

The acidic aqueous layer was treated in the manner described in Example2, above. The crude hydrochloride addition salt thus obtained wasrecrystallized from a mixture of methyl ethyl ketone and methanol togive 3.4 g. of 1-t-butyl-2,2-dimethyl-3-phenylazetidine hydrochloridehaving a melting point of about 186l89 C.

Analysis.-Calcd.: C, 70.98%; H, 9.53%; N, 5.52%. Found: C, 70.73%; H,9.82%; N, 5.67%.

EXAMPLE 8 1-t-butyl-2,2-dimethyl-3-phenyl-3-azetidinol hydrochloride Thesubject compound was prepared by adding ca. 3.0 g. of1-t-butyl-2,2-dimethyl-3-a2etidinone to an excess of phenyllithium inanhydrous ether. The reaction was worked up by adding a slurry of iceand water, and the crude amine was extracted with about 100 ml. ofether. The ether solvent was removed in vacuo and any water remainingwas removed by azeotropic distillation with about ml. of benzene.

To a 100-ml. benzene solution of the crude product,

ethanolic hydrogen chloride was added dropwise until the mixture testedacid. The solvents were removed in vacuo and the residual solid wasrecrystallized from a mixture of methyl ethyl ketone and methanol togive 1.45 g. of l-t-butyl 2,2 dimethy1-3-phenyl-3-azetidinolhydrochloride having a melting point of about 198 C.

(dec.).

Analysis.Calcd.: C, 66.77%; H, 8.47%; N, 5.19%. Found: C, 66.48%; H,9.19%; N, 5.09%.

EXAMPLE 9 3-ethylamino-3-methyl-1-chloro-2-butanone hydrochloride Twentygrams of 3-ethylamino-3-methyl-2-butanone hydrochloride were placed in asuitably equipped 500 ml., three-neck flask, and about 200 ml. ofglacial acetic acid were added with stirring. Complete solution of thesolid salt was obtained. Dry hydrogen chloride gas was passed into thesolution for about 20 minutes. Chlorine gas was then passed into thereaction mixture for about three hours with continuous stirring, afterwhich the reaction mixture was warmed for a period of time with a hotwater bath.

When the reaction was complete, the mixture was cooled to 0 C. The solidwhich separated was filtered off. Repeated ether washings removed anyfrozen acetic acid which might have been collected in the filtration. Asecond crop of crude, crystalline product was recovered from thefiltrate. The two crops of crystals were combined and recrystallizedfrom a mixture of methyl ethyl ketone and methanol to give 11.7 g. of3-ethylamino-3-methyl- 1-chl0ro-2-butanone hydrochloride having amelting point of about 204-205 C.

Analysis.Calcd.: C, 42.02%; H, 7.56%; N, 7.00%. Found: C, 42.38%; H,7.54%;N, 7.56%.

EXAMPLE 10 1-ethyl-2,2-dimethyl-3-azetidinone Following the procedure asoutlined in Example 2, but using 11.0 g. of3-ethylamino-3-methyl-1-chloro-2- butanone hydrochloride dissolved inabout 150 ml. of methanol and 10 g. of sodium bicarbonate dissolved inthe minimum amount of water as principal reactants,1-ethyl-2,2-dimethyl-3-azetidinone was obtained. A small amount of thefree base, dissolved in benzene, was used to prepare the hydrochlorideaddition salt, 1-ethyl-2,2- dimethyl-3-azetidinone hydrochloride, whichwas obtained as an uncrystallizable gum. The non-crystalline productgave a peak in the infrared absorption curve (1835 CH1. 1) correspondingto that required for the carbonyl group in a molecule having the3-azetidinone structure.

The crude free base darkened rapidly on standing, so was usedimmediately as described in the succeeding example.

EXAMPLE 11 1-ethyl-2,2-dimethyl-3-phenyl-3-azetidinol A solution of 18.5g. of the crude 1-ethyl-2,2-dimethyl- 3-azetidinone in ml. of dry etherwas added to an excess of phenyllithium in about 100 ml. of anhydrousether.

An ice-water slurry was added to decompose the reaction product mixtureand the crude free base was extracted with about ml. of ether. Thesolvent was evaporated in vacuo and the residual oil dried in the mannerdescribed in previous examples.

The hydrochloride addition salt was prepared by dropwise addition ofethanolic hydrogen chloride to the dry benzene solution of the free baseuntil the mixture was acidic. The solvents were removed in vacuo and theresidual solid was recrystallized from a mixture of methyl ethyl ketoneand methanol to yield 4.3 g. of 1-ethyl-2,2-dimethyl-3-phenyl-3-azetidinol hydrochloride having a melting point ofabout 210211 C. (dec.).

9 AnaIysis.Calcd.: C, 64.57%; H, 8.34%. Found: C, 64.38%; H, 3.44%.

EXAMPLE 12 3-methylamino-3 -methyl- 1-bromo-2-butanone Found: C,

EXAMPLE 13 1,2,2-trimethyl-3-azetidinone Following the same procedure asdescribed in Example 2, but using 3-methylamino-3-methyl-l-bromo-Z-butanone hydrobromide and sodium bicarbonate as the principal reactants,1,2,2-trimethyl-3-azetidinone was prepared. The structure was confirmedby the infrared and nuclear magnetic resonance spectra.

EXAMPLE 14 1,2,2-trimethyl-3,3-azetidinediol hydrochloride Using asample of the crude 1,2,2-trimethyl-3azetidinone (from Example 13) andfollowing the procedure of Example 3, the crystalline product, ahydrate, 1,2,2-trimethyl-3,3-azetidinediol hydrochloride, identified byinfrared spectral analysis, was obtained.

EXAMPLE 15 3-amino-3-methyl-1-bromo-2-butanone By the same procedure asdescribed in Example 1, but using 3-amino-3-methyl-2-butanonehydrobromide and bromine as the principal reactants,3-amino-3-methyll-bromo-Z-bntanone hydrobromide was prepared. A samplefor analysis, recrystallized from isopropanol, had a melting point ofabout 150-152 C.

Analysis.--Calcd.: C, 23.01%; H, 4.25%; Br, 61.24%. Found: C, 23.01%; H,4.20%; Br, 61.45%.

EXAMPLE 16 2,2-dimethyl-3-cyano-3-azetidinol To a solution of 27.6 g. ofsodium bisulfite in a minimal amount of water were added 23 g. of3-amino- 3-methyl-l-bromo-Z-butanone hydrobromide. The solution wasstirred for one hour at room temperature and a solution of 17.4 g. ofsodium cyanide in a small amount of water was added. The reactionmixture warmed slightly. The reaction mixture was stirred for anadditional hour. It was then extracted with ether continuouslyovernight. The ether layer was separated and concentrated in vacuo. Oncooling, a crude, crystalline product separated and was recrystallizedfrom acetone. The product, which weighed 2.4 g., was identified by theinfrared spectrum as being 2,2-dimethyl-3-cyano-3-azetidinol.

EXAMPLE 17 1,2,2-trimethyl-3-cyano-3-dimethylamino azetidine In thisexample the basic procedure of Example 2 was followed but using 23.7 g.of 3-methylamino-3-methyl- 1-bromo-2-butanone hydrobromide and 24 g. ofsodium cyanide in 100 ml. of dimethylformamide.

The reaction product mixture was made very strongly basic with aqueoussodium hydroxide solution, then stirred overnight with added sodiumchloride to aid in salting out the product. Continuous ether extractionwas then carried out for a 3-day period.

The ether extract was treated with dry hydrogen chloride gas and theprecipitated solid filtered 01f. This solid was dissolved in water, theaqueous solution hasified with sodium hydroxide, and the mixtureextracted with ether. The ether solution was dried, concentrated, andfractionated in vacua through a 24-inch spinning band column to yield aproduct having a boiling point of about 101-102 C./1112 mm. The materialsolidified on standing and had a melting point of about 4243 C. Theproduct was identified by its infrared and nuclear magnetic resonance(NMR) spectra as 1,2,2-trimethyl 3 cyano 3 dimethylamino azetidine. TheNMR spectrum showed five methyl groups.

From these results, it appeared that hydrolysis of the solvent,dimethylformamide, had occurred during the 3- day continuous etherextraction, releasing dimethylamine in the reaction product mixture andallowing the dimethylamine to complicate the reaction and produce thecom pound obtained.

I claim:

1. A compound represented by the following formula:

B -NH tir R O X wherein R and R when taken separately, are C C alkyl,C4C8 cycloalkyl, alkoxy(C C )alkyl, or phenyl;

R and R when taken together with the carbon atom to which they areattached, are C C cycloalkyl;

R is hydrogen, C -C alkyl, C C cycloalkyl, or

phenyl;

R is hydrogen, C -C alkyl, C C cycloalkyl, or

alkoxy (C -C alkyl;

X is bromine or chlorine; or the acid addition salts thereof.

2. The acid addition salt of claim 1 which is the hydrobromide salt ofthe compound or" claim 1 wherein R is t-butyl, each of R and R ismethyl, X is bromo, and R is hydrogen.

3. The acid addition salt of claim 1 which is the hydrochloride salt ofthe compound of claim 1 wherein R is ethyl, each of R and R is methyl, Xis chloro, and R is hydrogen.

4. The compound of claim 1 wherein each of R R and R is methyl, X ishromo, and R is hydrogen.

5. The compound of claim 1 wherein each of R and R is hydrogen, each ofR and R is methyl, and X is bromo.

References Cited UNITED STATES PATENTS 3,067,101 12/1962 Easton et al.3,111,542 11/1963 Doran et al. 3,254,124 5/1966 Stevens.

OTHER REFERENCES Tiffany et al., Chemical Abstracts, vol. 51, p. 11,285f1957).

Magidson et al., Chemical Abstracts, vol. 54, p. 12,144i to 12,145a(1960).

CHARLES B. PARKER, Primary Examiner R. L. RAYMOND, Assistant ExaminerUS. Cl. X.R.

